Shock wave lithotripsy (SWL) revolutionized the treatment of kidney stones when it was introduced in the 1980s. However, the subsequent development of the technology has shown little improvement in clinical outcomes, such as stone free rate. Further there have been studies indicating an association with chronic complications in particular new onset hypertension and diabetes mellitus. Progress within the current funding period has identified strategies by which shock waves can be delivered with reduced acute tissue damage. The goal of Project 4 is to investigate the fundamental mechanisms of tissue damage, both to the kidney, where the PPG has confirmed its extent and identified possible chronic implication, and in the pancreas. In Aim 1 we will extend a current numerical simulation tool to predict the acoustic insult of a lithotripter to the kidney and pancreas. This tool will be used extensively to provide input data for other aims. In Aim 2, will evaluate a hypothesis developed by this group that the direct effect of repeated shocks on the tissue might initiate injury. Preliminary results from a mathematical model predict that this damage will be more important in the inner medulla where injury is first observed experimentally. In Aim 3 we will use our advanced modeling and simulation tools to understand the mediating factors in cavitation induced injury. Experimental evidence of cavitation in tissue is unambiguous, but the mechanisms by which it damages tissue and the reasons why it appears suppressed during the first few hundred shock waves are unclear. Aim 4 will apply the tools developed in the previous 3 aims to assess the acoustic insult and subsequent tissue injury to the pancreas in order to gain insight into the risk of lithotripsy inducing diabetes. Aim 5 is motivated by data from the PPG that indicates that a broad focal zone lithotripter can suppress injury and at the same time improve stone fragmentation. The goal will be to understand the physical properties of the acoustic field which result in reduced tissue damage but with effective fragmentation. Aim 6 exploits data that shows many shock waves do not hit the stone but they will still impact tissue. We plan to develop a device that can track stone location and gate current lithotripters to ensure that shock waves are only fired when the stone is on target. By reducing the number of off-target shock waves the insult to the tissue will be reduced. The overarching goal of Project 4 is to provide a strategy for shock wave lithotripsy to be delivered with fewer side effects by a combination of understanding the fundamental mechanics of the tissue damage process and developing novel technologies which will reduce the shock wave impact.